结合RAGE和RIPK1诱导慢性高血糖症衍生的神经炎症的认知缺陷
Xiaoyan Zhou1, Yandong Zhu2, Lin Gao2
1Xuzhou Engineering Research Center of Medical Genetics and Transformation, Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu, China.
CNS neuroscience & therapeutics
|September 4, 2023
概括
先进糖化终产品 (RAGE) 的受体在海马中直接结合RIPK1,导致神经炎症和糖尿病的认知缺陷. 针对这种RAGE-RIPK1相互作用可能会改善糖尿病患者的大脑功能.
科学领域:
- 神经科学是一个神经科学.
- 免疫学 免疫学 免疫学
- 内分泌学 在内分泌学.
背景情况:
- 糖尿病中慢性高血糖会导致海马神经炎症,导致认知缺陷.
- 先进糖化终产品 (RAGE) 的受体与这种炎症过程和认知衰退有关.
- 了解RAGE介导的神经炎症的精确分子机制对于开发治疗策略至关重要.
研究的目的:
- 阐明RAGE在糖尿病引起的认知障碍期间调节海马中神经炎症的机制.
- 研究与受体相互作用的氨酸/氨酸蛋白激酶1 (RIPK1) 作为微质中的潜在RAGE结合伙伴的作用.
主要方法:
- 使用db/db小鼠作为2型糖尿病的模型.
- 采用GST拉下测试和AutoDock Vina模拟来识别RAGE和RIPK1.1之间的绑定域.
- 应用了西式涂抹,共免疫沉 (Co-IP) 和免疫光 (IF) 来确认蛋白质相互作用和水平.
- 使用行为测试评估认知功能:莫里斯水迷宫 (MWM),新物体识别 (NOR) 和恐惧调节.
主要成果:
- 通过氨基酸序列 (AAs) 362-367.7确定了RAGE和RIPK1之间的直接结合相互作用.
- 证明这种RAGE-RIPK1相互作用可以调节RIPK1的酸化,从而激活微质中的NLRP3炎症酶.
- 显示突变RAGE AAs 362-367逆转神经炎症,改善糖尿病小鼠的认知功能.
- 证实,高血糖引起的海马炎症取决于RAGE和RIPK1.1的直接结合.
结论:
- 通过AAs 362-367的RAGE和RIPK1之间的直接相互作用是推动高血糖环境中神经炎症的关键机制.
- 这种RAGE-RIPK1相互作用代表了糖尿病相关认知缺陷的发病过程中的关键分子节点.
- 准RAGE-RIPK1结合接口为减轻糖尿病认知障碍提供了潜在的治疗途径.
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